Submissions for variant NM_001001557.4(GDF6):c.1322A>G (p.Tyr441Cys)

gnomAD frequency: 0.00005  dbSNP: rs752600101

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001347939	SCV001542221	uncertain significance	Klippel-Feil syndrome 1, autosomal dominant; Isolated microphthalmia 4; Microphthalmia, isolated, with coloboma 6; Leber congenital amaurosis 17	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 441 of the GDF6 protein (p.Tyr441Cys). This variant is present in population databases (rs752600101, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with GDF6-related conditions. ClinVar contains an entry for this variant (Variation ID: 1043780). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GDF6 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001573001	SCV001798250	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001573001	SCV001963449	uncertain significance	not provided		no assertion criteria provided	clinical testing